The natural history of human cancers is characterized by the progressive selection and outgrowth of cells that possess increasingly aggressive properties. This process ultimately leads to resistance to therapeutic agents, distant metastasis, and tumor recurrence. Together, these three manifestations of tumor progression are responsible for the vast majority of cancer deaths. Indeed, metastasis is the proximate cause of death for most of the 282,000 people each year in the United States who succumb to cancers of the breast, lung, prostate, and colon. Nevertheless, while tumor progression constitutes a problem of unrivaled clinical importance, the mechanisms underlying it are largely unknown. As such, elucidating the molecular, cellular, and pathophysiological events that contribute to this process is a critical priority in cancer research. The principal goal of this proposal is to develop new conceptual and technical approaches for understanding the mechanisms of tumor progression and metastasis. To accomplish this, the proposed program will employ a broad array of state-of-the-art cellular and molecular in vivo imaging approaches to analyze several genetically engineered mouse models for breast cancer progression developed by the investigators of this program, including a series of inducible transgenic models that permits the ordered, temporal dissection of each of the stages of mammary tumorigenesis and tumor progression as driven by defined oncogenic pathways. This proposal represents a highly integrated translational effort to image and understand tumor progression, tumor metastasis, and tumor response to therapy by using computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), single photon emission computed tomography (SPECT), ultrasound (US), bioluminescence imaging, and optical methods for measuring gene expression and mitochondrial redox potential. Specific goals of this program include development of the technology required to visualize and follow a tumor cell in vivo from its origins through its progression to distant metastasis, the ability to assess tumor response to therapy over time and predict clinical outcome, and the development of novel platforms for imaging the activity of molecular pathways relevant to human cancers. Finally, while this proposal is focused on breast cancer, the mechanisms, processes, approaches, and findings from the proposed studies will undoubtedly be applicable to most solid tumors. Without question, the biological and technical challenges to studying tumor progression and metastasis are considerable, likely explaining why this field has been termed "one of the last great frontiers of cancer biology". The group of 25 investigators from 6 institutions assembled for this project provides the necessary breadth and depth required for this challenge. We believe that combining state-of-the-art mouse modeling approaches with genomics, histopathology, and a comprehensive set of non-invasive imaging methods has the power and promise to revolutionize our understanding of cancer etiology, progression, metastasis, recurrence, and response to therapy.